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Isoflurane favorably modulates guanosine triphosphate cyclohydrolase-1 and endothelial nitric oxide synthase during myocardial ischemia and reperfusion injury in rats.

AbstractBACKGROUND:
The authors investigated the hypothesis that isoflurane modulates nitric oxide (NO) synthesis and protection against myocardial infarction through time-dependent changes in expression of key NO regulatory proteins, guanosine triphosphate cyclohydrolase (GTPCH)-1, the rate-limiting enzyme involved in the biosynthesis of tetrahydrobiopterin and endothelial nitric oxide synthase (eNOS).
METHODS:
Myocardial infarct size, NO production (ozone-mediated chemiluminescence), GTPCH-1, and eNOS expression (real-time reverse transcriptase polymerase chain reaction and western blotting) were measured in male Wistar rats with or without anesthetic preconditioning (APC; 1.0 minimum alveolar concentration isoflurane for 30 min) and in the presence or absence of an inhibitor of GTPCH-1, 2,4-diamino-6-hydroxypyrimidine.
RESULTS:
NO2 production (158 ± 16 and 150 ± 13 pmol/mg protein at baseline in control and APC groups, respectively) was significantly (P < 0.05) increased 1.5 ± 0.1 and 1.4 ± 0.1 fold by APC (n = 4) at 60 and 90 min of reperfusion, respectively, concomitantly, with increased expression of GTPCH-1 (1.3 ± 0.3 fold; n = 5) and eNOS (1.3 ± 0.2 fold; n = 5). In contrast, total NO (NO2 and NO3) was decreased after reperfusion in control experiments. Myocardial infarct size was decreased (43 ± 2% of the area at risk for infarction; n = 6) by APC compared with control experiments (57 ± 1%; n = 6). 2, 4-Diamino-6-hydroxypyrimidine decreased total NO production at baseline (221 ± 25 and 175 ± 31 pmol/mg protein at baseline in control and APC groups, respectively), abolished isoflurane-induced increases in NO at reperfusion, and prevented reductions of myocardial infarct size by APC (60 ± 2%; n = 6).
CONCLUSION:
APC favorably modulated a NO biosynthetic pathway by up-regulating GTPCH-1 and eNOS, and this action contributed to protection of myocardium against ischemia and reperfusion injury.
AuthorsInes Baotic, Dorothee Weihrauch, Jesse Procknow, Jeanette Vasquez-Vivar, Zhi-Dong Ge, Shaan Sudhakaran, David C Warltier, Judy R Kersten
JournalAnesthesiology (Anesthesiology) Vol. 123 Issue 3 Pg. 582-9 (Sep 2015) ISSN: 1528-1175 [Electronic] United States
PMID26192027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anesthetics, Inhalation
  • Isoflurane
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • GTP Cyclohydrolase
Topics
  • Anesthetics, Inhalation (administration & dosage)
  • Animals
  • GTP Cyclohydrolase (biosynthesis)
  • Isoflurane (administration & dosage)
  • Male
  • Myocardial Ischemia (drug therapy, enzymology)
  • Myocardial Reperfusion Injury (drug therapy, enzymology)
  • Nitric Oxide Synthase Type III (biosynthesis)
  • Random Allocation
  • Rats
  • Rats, Wistar

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